# US 10,117,881 B2 · Protective effect of DMPC, DMPG, DMPC/DMPG, LYSOPG and LYSOPC against drugs that cause channelopathies

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- Number: US 10,117,881 B2
- Document ID: US10117881B2
- Status: Granted
- Kind: B2
- Application number: 15/347,381
- Filed: 2016-11-09
- Published: 2017-04-06
- Granted: 2018-11-06
- Earliest claimed: 2011-06-03
- Assignees: Signpath Pharma, Inc.
- Applicants: SignPath Pharma Inc.
- Inventors: Lawrence Helson
- Web page: https://patentgrep.com/patent/US10117881B2

## CPC

- A61K 31/683: Diesters of a phosphorus acid with two hydroxy compounds, e.g. phosphatidylinositols
- A61K 9/127: Synthetic bilayered vehicles, e.g. liposomes or liposomes with cholesterol as the only non-phosphatidyl surfactant
- A61K 31/445: Non condensed piperidines, e.g. piperocaine
- A61K 31/506: not condensed and containing further heterocyclic rings
- A61K 31/685: one of the hydroxy compounds having nitrogen atoms, e.g. phosphatidylserine, lecithin
- G01N 33/5088: {of vertebrates}
- G01N 2800/326: Arrhythmias, e.g. ventricular fibrillation, tachycardia, atrioventricular block, torsade de pointes
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- G01N: INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES (measuring or testing apparatus or processes other than immunoassay, involving enzymes or microorganisms C12M, C12Q)

## Abstract

The present invention includes compositions and methods for preventing one or more cardiac channelopathies or conditions resulting from irregularities or alterations in cardiac patterns caused by an active agent or a drug in a human or animal subject comprising: an amount of a lysophosphatidylglycerol adapted for oral administration effective to reduce or prevent one or more cardiac channelopathies or conditions resulting from irregularities or alterations in cardiac patterns caused by the active agent or drug.

## Claims

### Claim 1

A composition consisting of:
one or more pharmacologically active agents provided in an amount that induce a cardiac channelopathy or a condition resulting from the irregularity or alteration in the cardiac pattern selected from QTc, LQT2, LQTS, or torsades de pointes in a subject and one or more lipids provided in an amount sufficient to prevent or reduce the cardiac channelopathy or the condition resulting from the irregularity or alteration in the cardiac pattern caused by the one or more pharmacologically active agents in a formulation, wherein the formulation is dispersed in a pharmaceutically acceptable medium, solvent, or vehicle, wherein the active agent, the lipids, or both are dissolved, dispersed, or suspended in the medium, the solvent, or the vehicle, wherein the lipids reduce or prevent the cardiac channelopathy or a condition resulting from the irregularity or alteration in the cardiac pattern.

### Claim 2 (depends on 1)

The composition of claim 1, wherein the one or more pharmacologically active agents is selected from at least one of 5-HT3 antagonists that block serotonin binding, 5-HT4 receptor agonists, histamine antagonists, calcium channel blockers, anti-malarial agents, antipsychotic agents, halodols, antibiotics, anti-arrhythmics, anti-cancer agents, opioids, or hypolipidemic agents.

### Claim 3 (depends on 1)

The composition of claim 1, wherein the lipid comprises at least one of a phosphatidylcholine, a phosphatidylethanolamine, a phosphatidylserine, a phosphatidylglycerol, a cardiolipin, a phosphatidylinositol or a precursor thereof.

### Claim 4 (depends on 1)

The composition of claim 1, wherein the lipid comprises a lysophosphatidylglycerol, a lysophosphatidylcholine, lauroyl-lysophosphatidylcholine, myristoyl-lysophosphatidylcholine, palmitoyl-lysophosphatidylcholine, stearoyl-lysophosphatidylcholine, arachidoyl-lysophosphatidylcholine, oleoyl-lysophosphatidylcholine, linoleoyl-lysophosphatidylcholine, linolenoyl-lysophosphatidylcholine, erucoyl-lysophosphatidylcholine, 1-Myristoyl-2-Hydroxy-sn-Glycero-3-Phosphocholine, 1,2-Dimyristoyl-sn-glycero-3-phosphorylcholine (DMPC), 1,2-Mysteroyl-2-Hydroxy-sn-Glycero-3-[Phospho-rac-(glycerol)], 1,2-Dimyristoyl-sn-glycero-3-phosphorylglycerol (DMPG), DMPC/DMPG, 1-myristoyl-2-hydroxy-sn-glycero-3-phospho-(1′-rac-glycerol) (LysoPG), or 1-myristoyl-2-hydroxy-sn-glycero-3-phosphocholine (LysoPC).

### Claim 5 (depends on 1)

The composition of claim 1, wherein the active agent drug is selected from at least one of crizotinib, nilotinib, terfenadine, astemizole, gripafloxacin, terodilene, droperidole, lidoflazine, levomethadyl, sertindoyle or cisapride.

### Claim 6 (depends on 1)

The composition of claim 1, wherein the composition is adapted for enteral, parenteral, intravenous, intraperitoneal, cutaneous, subcutaneous, pulmonary, rectal, vaginal, or oral administration.

### Claim 7 (depends on 1)

The composition of claim 1, wherein the active agent is provided in a lipid that is formed into a liposome, wherein the lipid is selected from at least one of phosphatidylcholine, lysolecithin, lysophosphatidylethanol-amine, phosphatidylserine, phosphatidylinositol, sphingomyelin, phosphatidylethanolamine, cardiolipin, phosphatidic acid, cerebrosides, dicetylphosphate, phosphatidylcholine, and dipalmitoyl-phosphatidylglycerol, stearylamine, dodecylamine, hexadecyl-amine, acetyl palmitate, glycerol ricinoleate, hexadecyl sterate, isopropyl myristate, amphoteric acrylic polymers, fatty acid, fatty acid amides, cholesterol, cholesterol ester, diacylglycerol, or diacylglycerol succinate.

### Claim 8 (depends on 1)

The composition of claim 1, wherein the active agent is selected from Albuterol, Alfuzosin, Amantadine, Amiodarone, Amisulpride, Amitriptyline, Amoxapine, Amphetamine, Anagrelide, Apomorphine, Arformoterol, Aripiprazole, Arsenic trioxide, Astemizole, Atazanavir, Atomoxetine, Azithromycin, Bedaquiline, Bepridil, Bortezomib, Bosutinib, Chloral hydrate, Chloroquine, Chlorpromazine, Ciprofloxacin, Cisapride, Citalopram, Clarithromycin, Clomipramine, Clozapine, Curcumin, Crizotinib, Dabrafenib, Dasatinib, Desipramine, Dexmedetomidine, Dexmethylphenidate, Dextroamphetamine, d-Amphetamine, Dihydroartemisinin and Piperaquine, Diphenhydramine, Disopyramide, Dobutamine, Dofetilide, Dolasetron, Domperidone, Dopamine, Doxepin, Dronedarone, Droperidol, Ephedrine, Epinephrine, Adrenaline, Eribulin, Erythromycin, Escitalopram, Famotidine, Felbamate, Fenfluramine, Fingolimod, Flecainide, Fluconazole, Fluoxetine, Formoterol, Foscarnet, Fosphenytoin, Furosemide, Frusemide, Galantamine, Gatifloxacin, Gemifloxacin, Granisetron, Halofantrine, Haloperidol, Hydrochlorothiazide, Ibutilide, Iloperidone, Imipramine, Melipramine, Indapamide, Isoproterenol, Isradipine, Itraconazole, Ivabradine, Ketoconazole, Lapatinib, Levalbuterol, Levofloxacin, Levomethadyl, Lisdexamfetamine, Lithium, Mesoridazine, Metaproterenol, Methadone, Methamphetamine, Methylphenidate, Midodrine, Mifepristone, Mirabegron, Mirtazapine, Moexipril/HCTZ, Moxifloxacin, Nelfinavir, Nicardipine, Nilotinib, Norepinephrine (noradrenaline), Norfloxacin, Nortriptyline, Ofloxacin, Olanzapine, Ondansetron, Oxytocin, Paliperidone, Paroxetine, Pasireotide, Pazopanib, Pentamidine, Perflutren lipid microspheres, Phentermine, Phenylephrine, Phenylpropanolamine, Pimozide, Posaconazole, Probucol, Procainamide, Promethazine, Protriptyline, Pseudoephedrine, Quetiapine, Quinidine, Quinine sulfate, Ranolazine, Rilpivirine, Risperidone, Ritodrine, Ritonavir, Roxithromycin, Salbutamol, Salmeterol, Saquinavir, Sertindole, Sertraline, Sevoflurane, Sibutramine, Solifenacin, Sorafenib, Sotalol, Sparfloxacin, Sulpiride, Sunitinib, Tacrolimus, Tamoxifen, Telaprevir, Telavancin, Telithromycin, Terbutaline, Terfenadine, Tetrabenazine, Thioridazine, Tizanidine, Tolterodine, Toremifene, Trazodone, Trimethoprim-Sulfa, Trimipramine, Vandetanib, Vardenafil, Vemurafenib, Venlafaxine, Voriconazole, Vorinostat, or Ziprasidone.

### Claim 9

A composition consisting of:
one or more pharmacologically active agents provided in an amount that induce a cardiac channelopathy or a condition resulting from the irregularity or alteration in the cardiac pattern in a subject and one or more lipids provided in an amount sufficient to prevent or reduce the cardiac channelopathy or the condition resulting from the irregularity or alteration in the cardiac pattern caused by the one or more pharmacologically active agents in a formulation, wherein the formulation is dispersed in a pharmaceutically acceptable medium, solvent, or vehicle, wherein the active agent, the lipids, or both are dissolved, dispersed, or suspended in the medium, the solvent, or the vehicle, wherein the lipids form empty liposomes that reduce or prevent the cardiac channelopathy or a condition resulting from the irregularity or alteration in the cardiac pattern, wherein the active agent is selected from Albuterol, Alfuzosin, Amantadine, Amiodarone, Amisulpride, Amitriptyline, Amoxapine, Amphetamine, Anagrelide, Apomorphine, Arformoterol, Aripiprazole, Arsenic trioxide, Astemizole, Atazanavir, Atomoxetine, Azithromycin, Bedaquiline, Bepridil, Bortezomib, Bosutinib, Chloral hydrate, Chloroquine, Chlorpromazine, Ciprofloxacin, Cisapride, Citalopram, Clarithromycin, Clomipramine, Clozapine, Curcumin, Crizotinib, Dabrafenib, Dasatinib, Desipramine, Dexmedetomidine, Dexmethylphenidate, Dextroamphetamine, d-Amphetamine, Dihydroartemisinin and Piperaquine, Diphenhydramine, Disopyramide, Dobutamine, Dofetilide, Dolasetron, Domperidone, Dopamine, Doxepin, Dronedarone, Droperidol, Ephedrine, Epinephrine, Adrenaline, Eribulin, Erythromycin, Escitalopram, Famotidine, Felbamate, Fenfluramine, Fingolimod, Flecainide, Fluconazole, Fluoxetine, Formoterol, Foscarnet, Fosphenytoin, Furosemide, Frusemide, Galantamine, Gatifloxacin, Gemifloxacin, Granisetron, Halofantrine, Haloperidol, Hydrochlorothiazide, Ibutilide, Iloperidone, Imipramine, Melipramine, Indapamide, Isoproterenol, Isradipine, Itraconazole, Ivabradine, Ketoconazole, Lapatinib, Levalbuterol, Levofloxacin, Levomethadyl, Lisdexamfetamine, Lithium, Mesoridazine, Metaproterenol, Methadone, Methamphetamine, Methylphenidate, Midodrine, Mifepristone, Mirabegron, Mirtazapine, Moexipril/HCTZ, Moxifloxacin, Nelfinavir, Nicardipine, Nilotinib, Norepinephrine, Norfloxacin, Nortriptyline, Ofloxacin, Olanzapine, Ondansetron, Oxytocin, Paliperidone, Paroxetine, Pasireotide, Pazopanib, Pentamidine, Perflutren lipid microspheres, Phentermine, Phenylephrine, Phenylpropanolamine, Pimozide, Posaconazole, Probucol, Procainamide, Promethazine, Protriptyline, Pseudoephedrine, Quetiapine, Quinidine, Quinine sulfate, Ranolazine, Rilpivirine, Risperidone, Ritodrine, Ritonavir, Roxithromycin, Salbutamol, Salmeterol, Saquinavir, Sertindole, Sertraline, Sevoflurane, Sibutramine, Solifenacin, Sorafenib, Sotalol, Sparfloxacin, Sulpiride, Sunitinib, Tacrolimus, Tamoxifen, Telaprevir, Telavancin, Telithromycin, Terbutaline, Terfenadine, Tetrabenazine, Thioridazine, Tizanidine, Tolterodine, Toremifene, Trazodone, Trimethoprim-Sulfa, Trimipramine, Vandetanib, Vardenafil, Vemurafenib, Venlafaxine, Voriconazole, Vorinostat, and Ziprasidone.

### Claim 10 (depends on 9)

The composition of claim 9, wherein the one or more pharmacologically active agents is selected from at least one of 5-HT3 antagonists that block serotonin binding, 5-HT4 receptor agonists, histamine antagonists, calcium channel blockers, anti-malarial agents, antipsychotic agents, halodols, antibiotics, anti-arrhythmics, anti-cancer agents, opioids, or hypolipidemic agents.

### Claim 11 (depends on 9)

The composition of claim 9, wherein the lipid comprises at least one of a phosphatidylcholine, a phosphatidylethanolamine, a phosphatidylserine, a phosphatidylglycerol, a cardiolipin, a phosphatidylinositol or a precursor thereof.

### Claim 12 (depends on 9)

The composition of claim 9, wherein the lipid comprises a lysophosphatidylglycerol, a lysophosphatidylcholine, lauroyl-lysophosphatidylcholine, myristoyl-lysophosphatidylcholine, palmitoyl-lysophosphatidylcholine, stearoyl-lysophosphatidylcholine, arachidoyl-lysophosphatidylcholine, oleoyl-lysophosphatidylcholine, linoleoyl-lysophosphatidylcholine, linolenoyl-lysophosphatidylcholine, erucoyl-lysophosphatidylcholine, 1-Myristoyl-2-Hydroxy-sn-Glycero-3-Phosphocholine, 1,2-Dimyristoyl-sn-glycero-3-phosphorylcholine (DMPC), 1,2-Mysteroyl-2-Hydroxy-sn-Glycero-3-[Phospho-rac-(glycerol)], 1,2-Dimyristoyl-sn-glycero-3-phosphorylglycerol (DMPG), DMPC/DMPG, 1-myristoyl-2-hydroxy-sn-glycero-3-phospho-(1′-rac-glycerol) (LysoPG), or 1-myristoyl-2-hydroxy-sn-glycero-3-phosphocholine (LysoPC).

### Claim 13 (depends on 9)

The composition of claim 9, wherein the cardiac channelopathy or the condition resulting from the irregularity or alteration in the cardiac pattern is prolongation of the QTc, LQT2, LQTS, or torsades de pointes.

### Claim 14 (depends on 9)

The composition of claim 9, wherein the composition is adapted for enteral, parenteral, intravenous, intraperitoneal, cutaneous, subcutaneous, pulmonary, rectal, vaginal, or oral administration.

### Claim 15

A composition consisting of:
one or more pharmacologically active agents provided in an amount that induce a cardiac channelopathy or a condition resulting from the irregularity or alteration in the cardiac pattern selected from QTc, LQT2, LQTS, and torsades de pointes in a subject and one or more lipids provided in an amount sufficient to prevent or reduce the cardiac channelopathy or the condition resulting from the irregularity or alteration in the cardiac pattern caused by the one or more pharmacologically active agents in an intravenous formulation, wherein the formulation is dispersed in a pharmaceutically acceptable medium, solvent, or vehicle, wherein the active agent, the lipids, or both are dissolved, dispersed, or suspended in the medium, the solvent, or the vehicle, wherein the active agent is selected from Albuterol, Alfuzosin, Amantadine, Amiodarone, Amisulpride, Amitriptyline, Amoxapine, Amphetamine, Anagrelide, Apomorphine, Arformoterol, Aripiprazole, Arsenic trioxide, Astemizole, Atazanavir, Atomoxetine, Azithromycin, Bedaquiline, Bepridil, Bortezomib, Bosutinib, Chloral hydrate, Chloroquine, Chlorpromazine, Ciprofloxacin, Cisapride, Citalopram, Clarithromycin, Clomipramine, Clozapine, Curcumin, Crizotinib, Dabrafenib, Dasatinib, Desipramine, Dexmedetomidine, Dexmethylphenidate, Dextroamphetamine, d-Amphetamine, Dihydroartemisinin and Piperaquine, Diphenhydramine, Disopyramide, Dobutamine, Dofetilide, Dolasetron, Domperidone, Dopamine, Doxepin, Dronedarone, Droperidol, Ephedrine, Epinephrine, Adrenaline, Eribulin, Erythromycin, Escitalopram, Famotidine, Felbamate, Fenfluramine, Fingolimod, Flecainide, Fluconazole, Fluoxetine, Formoterol, Foscarnet, Fosphenytoin, Furosemide, Frusemide, Galantamine, Gatifloxacin, Gemifloxacin, Granisetron, Halofantrine, Haloperidol, Hydrochlorothiazide, Ibutilide, Iloperidone, Imipramine, Melipramine, Indapamide, Isoproterenol, Isradipine, Itraconazole, Ivabradine, Ketoconazole, Lapatinib, Levalbuterol, Levofloxacin, Levomethadyl, Lisdexamfetamine, Lithium, Mesoridazine, Metaproterenol, Methadone, Methamphetamine, Methylphenidate, Midodrine, Mifepristone, Mirabegron, Mirtazapine, Moexipril/HCTZ, Moxifloxacin, Nelfinavir, Nicardipine, Nilotinib, Norepinephrine, Norfloxacin, Nortriptyline, Ofloxacin, Olanzapine, Ondansetron, Oxytocin, Paliperidone, Paroxetine, Pasireotide, Pazopanib, Pentamidine, Perflutren lipid microspheres, Phentermine, Phenylephrine, Phenylpropanolamine, Pimozide, Posaconazole, Probucol, Procainamide, Promethazine, Protriptyline, Pseudoephedrine, Quetiapine, Quinidine, Quinine sulfate, Ranolazine, Rilpivirine, Risperidone, Ritodrine, Ritonavir, Roxithromycin, Salbutamol, Salmeterol, Saquinavir, Sertindole, Sertraline, Sevoflurane, Sibutramine, Solifenacin, Sorafenib, Sotalol, Sparfloxacin, Sulpiride, Sunitinib, Tacrolimus, Tamoxifen, Telaprevir, Telavancin, Telithromycin, Terbutaline, Terfenadine, Tetrabenazine, Thioridazine, Tizanidine, Tolterodine, Toremifene, Trazodone, Trimethoprim-Sulfa, Trimipramine, Vandetanib, Vardenafil, Vemurafenib, Venlafaxine, Voriconazole, Vorinostat, and Ziprasidone.

### Claim 16 (depends on 15)

The composition of claim 15, wherein the one or more pharmacologically active agents is selected from at least one of 5-HT3 antagonists that block serotonin binding, 5-HT4 receptor agonists, histamine antagonists, calcium channel blockers, anti-malarial agents, antipsychotic agents, halodols, antibiotics, anti-arrhythmics, anti-cancer agents, opioids, or hypolipidemic agents.

### Claim 17 (depends on 15)

The composition of claim 15, wherein the lipid comprises at least one of a phosphatidylcholine, a phosphatidylethanolamine, a phosphatidylserine, a phosphatidylglycerol, a cardiolipin, a phosphatidylinositol or a precursor thereof.

### Claim 18 (depends on 15)

The composition of claim 15, wherein the lipid comprises a lysophosphatidylglycerol, a lysophosphatidylcholine, lauroyl-lysophosphatidylcholine, myristoyl-lysophosphatidylcholine, palmitoyl-lysophosphatidylcholine, stearoyl-lysophosphatidylcholine, arachidoyl-lysophosphatidylcholine, oleoyl-lysophosphatidylcholine, linoleoyl-lysophosphatidylcholine, linolenoyl-lysophosphatidylcholine, erucoyl-lysophosphatidylcholine, 1-Myristoyl-2-Hydroxy-sn-Glycero-3-Phosphocholine, 1,2-Dimyristoyl-sn-glycero-3-phosphorylcholine (DMPC), 1,2-Mysteroyl-2-Hydroxy-sn-Glycero-3-[Phospho-rac-(glycerol)], 1,2-Dimyristoyl-sn-glycero-3-phosphorylglycerol (DMPG), DMPC/DMPG, 1-myristoyl-2-hydroxy-sn-glycero-3-phospho-(1′-rac-glycerol) (LysoPG), or 1-myristoyl-2-hydroxy-sn-glycero-3-phosphocholine (LysoPC).